The present invention relates to compounds having pharmaceutical properties, and in particular, to compounds useful for preventing and treating central nervous system (CNS) disorders. The present invention relates to a method for treating patients suffering from or susceptible to such disorders, and in particular, to a method for treating patients suffering from those disorders which are associated with neurotransmitter system dysfunction. The present invention also relates to compositions of matter useful as pharmaceutical compositions in the prevention and treatment of CNS disorders which have been attributed to neurotransmitter system dysfunction.
CNS disorders are a type of neurological disorder. CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology. CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders. There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors). Several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency and/or a serotonergic deficiency. CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer""s disease), senile dementia (dementia of the Alzheimer""s type), Parkinsonism including Parkinson""s disease, Huntington""s chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette""s syndrome.
Senile dementia of the Alzheimer""s type (SDAT) is a debilitating neurodegenerative disease, mainly afflicting the elderly; characterized by a progressive intellectual and personality decline, as well as a loss of memory, perception, reasoning, orientation and judgment. One feature of the disease is an observed decline in the function of cholinergic systems, and specifically, a severe depletion of cholinergic neurons (i.e., neurons that release acetylcholine, which is believed to be a neurotransmitter involved in learning and memory mechanisms). See, Jones, et al., Intern. J. Neurosci., Vol. 50, p. 147 (1990); Perry, Br. Med. Bull., Vol. 42, p. 63 (1986) and Sitaram, et al., Science, Vol. 201, p. 274 (1978). It has been observed that nicotinic acetylcholine receptors, which bind nicotine and other nicotinic agonists with high affinity, are depleted during the progression of SDAT. See, Giacobini, J. Neurosci. Res., Vol. 27, p. 548 (1990); and Baron, Neurology, Vol. 36, p. 1490 (1986). As such, it would seem desirable to provide therapeutic compounds which either directly activate nicotinic receptors in place of acetylcholine or act to minimize the loss of those nicotinic receptors.
Certain attempts have been made to treat SDAT. For example, nicotine has been suggested to possess an ability to activate nicotinic cholinergic receptors upon acute administration, and to elicit an increase in the number of such receptors upon chronic administration to animals. See, Rowell, Adv. Behav. Biol., Vol. 31, p. 191 (1987); and Marks, J. Pharmacol. Exp. Ther., Vol. 226, p. 817 (1983). It also has been proposed that nicotine can act directly to elicit the release of acetylcholine in brain tissue, to improve cognitive functions, and to enhance attention. See, Rowell, et al., J. Neurochem., Vol. 43, p. 1593 (1984); Sherwood, Human Psychopharm., Vol. 8, pp. 155-184 (1993); Hodges, et al., Bio. of Nic., Edit. by Lippiello, et al., p. 157 (1991); Sahakian, et al., Br. J. Psych., Vol. 154, p. 797 (1989); and U.S. Pat. Nos. 4,965,074 to Leeson and 5,242,935 to Lippiello et al. Other methods for treating SDAT have been proposed, including U.S. Pat. Nos. 5,212,188 to Caldwell et al. and 5,227,391 to Caldwell et al. and European Patent Application No. 588,917. Another proposed treatment for SDAT is Cognex, which is a capsule containing tacrine hydrochloride, available from Parke-Davis Division of Warner-Lambert Company, which reportedly preserves existing acetylchloine levels in patients treated therewith.
Parkinson""s disease (PD) is a debilitating neurodegenerative disease, presently of unknown etiology, characterized by tremors and muscular rigidity. A feature of the disease appears to involve the degeneration of dopaminergic neurons (i.e., which secrete dopamine). One symptom of the disease has been observed to be a concomitant loss of nicotinic receptors which are associated with such dopaminergic neurons, and which are believed to modulate the process of dopamine secretion. See, Rinne, et al., Brain Res., Vol. 54, pp. 167-170 (1991) and Clark, et al., Br. J. Pharm., Vol. 85, pp. 827-835 (1985). It also has been proposed that nicotine can ameliorate the symptoms of PD. See, Smith et al., Rev. Neurosci., Vol. 3(1), pp. 25-43 (1982).
Certain attempts have been made to treat PD. One proposed treatment for PD is Sinemet CR, which is a sustained-release tablet containing a mixture of carbidopa and levodopa, available from The DuPont Merck Pharmaceutical Co. Another proposed treatment for PD is Eldepryl, which is a tablet containing selefiline hydrochloride, available from Somerset Pharmaceuticals, Inc. Another proposed treatment for PD is Parlodel, which is a tablet containing bromocriptine mesylate, available from Sandoz Pharmaceuticals Corporation. Another method for treating PD and a variety of other neurodegenerative diseases has been proposed in U.S. Pat. No. 5,210,076 to Berliner et al.
Tourette""s syndrome (TS) is an autosomal dominant neuropsychiatric disorder characterized by a range of neurological and behavioral symptoms. Typical symptoms include (i) the onset of the disorder before the age of 21 years, (ii) multiple motor and phonic tics although not necessarily concurently, (iii) varience in the clinical phenomenology of the tics, and (iv) occurrence of quasi daily tics throughout a period of time exceeding a year. Motor tics generally include eye blinking, head jerking, shoulder shrugging and facial grimacing; while phonic or vocal tics include throat clearing, sniffling, yelping, tongue clicking and uttering words out of context. The pathophysiology of TS presently is unknown, however it is believed that neurotransmission dysfunction is implicated with the disorder. See, Calderon-Gonzalez et al., Intern. Pediat., Vol. 8(2), pp. 176-188 (1993) and Oxford Textbook of Medicine, Eds. Weatherall et al., Chapter 21.218 (1987).
It has been proposed that nicotine pharmacology is beneficial in suppressing the symptoms associated with TS. See, Devor et al., The Lancet, Vol. 8670, p. 1046 (1989); Jarvik, British J. of Addiction, Vol. 86, pp. 571-575 (1991); McConville et al., Am. J. Psychiatry, Vol. 148 (6), pp. 793-794 (1991); Newhouse et al., Brit. J. Addic., Vol. 86, pp. 521-526 (1991); McConville et al., Biol. Psychiatry, Vol. 31, pp. 832-840 (1992); and Sanberg et al., Proceedings from Intl. Symp. Nic., S39 (1994). It also has been proposed to treat TS using Haldol, which is haloperidol available from McNeil Pharmaceutical; Catapres, which is clonidine available from Boehringer Ingelheim Pharmaceuticals, Inc.; Orap, which is pimozide available from Gate Pharmaceuticals; Prolixin, which is fluphenazine available from Apothecon Division of Bristol-Myers Squibb Co.; and Klonopin, which is clonazepam available from Hoffmann-LaRoche Inc.
Attention deficit disorder (ADD) is a disorder which affects mainly children, although ADD can affect adolescents and adults. See, Vinson, Arch. Fam. Med., Vol. 3(5), pp. 445-451 (1994); Hechtman, J. Psychiatry Neurosci., Vol. 19 (3), pp. 193-201 (1994); Faraone et al., Biol. Psychiatry, Vol. 35(6), pp. 398-402 (1994) and Malone et al., J. Child Neurol., Vol. 9(2), pp. 181-189 (1994). Subjects suffering from the disorder typically have difficulty concentrating, listening, learning and completing tasks; and are restless, fidgety, impulsive and easily distracted. Attention deficit disorder with hyperactivity (ADHD) includes the symptoms of ADD as well as a high level of activity (e.g., restlessness and movement). Attempts to treat ADD have involved administration of Dexedrine, which is a sustained release capsule containing detroamphetamine sulfate, available from SmithKline Beecham Pharmaceuticals; Ritalin, which is a tablet containing methylphenidate hydrochloride, available from Ciba Pharmaceutical Company; and Cylert, which is a tablet containing premoline, available from Abbott Laboratories. In addition, it has been reported that administration of nicotine to an individual improves that individual""s selective and sustained attention. See, Warburton et al., Cholinergic control of cognitive resources, Neuropsychobiology, Eds. Mendlewicz, et al., pp 43-46 (1993).
Schizophrenia is characterized by psychotic symptoms including delusions, catatonic behavior and prominent hallucinations, and ultimately results in a profound decline in the psychosocial affect of the subject suffering therefrom. Traditionally, schizophrenia has been treated with Klonopin, which is available as a tablet containing clonezepam, available from Hoffmann-LaRoche Inc.; Thorazine, which is available as a tablet containing chlorpromazine, available from SmithKline Beecham Pharmaceuticals; and Clozaril, which is a tablet containing clozapine, available from Sandoz Pharmaceuticals. Such neuroleptics are believed to be effective as a result of interaction thereof with the dopaminergic pathways of the CNS. In addition, a dopaminergic dysfunction possessed by individuals suffering from schizophrenia has been proposed. See, Lieberman et al., Schizophr. Bull., Vol. 19, pp. 371-429 (1993) and Glassman, Amer. J. Psychiatry, Vol. 150, pp. 546-553 (1993). Nicotine has been proposed as being effective in effecting neurotransmitter disfunction associated with schizophrenia. See, Merriam et al., Psychiatr. Annals, Vol. 23, pp. 171-178 (1993) and Adler et al., Biol. Psychiatry, Vol. 32, pp. 607-616 (1992).
Nicotine has been proposed to have a number of pharmacological effects. Certain of those effects may be related to effects upon neurotransmitter release. See, for example, Sjak-shie et al., Brain Res., Vol. 624, pp. 295-298 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al., J. Neurochem., Vol. 43, pp. 1593-1598 (1984); Rapier et al., J. Neurochem., Vol. 50, pp. 1123-1130 (1988); Sandor et al., Brain Res., Vol. 567, pp. 313-316 (1991) and Vizi, Br. J. Pharmacol., Vol. 47, pp. 765-777 (1973). Release of norepinephrine by neurons upon administration of nicotine has been reported by Hall et al., Biochem. Pharmacol., Vol. 21, pp. 1829-1838 (1972). Release of serotonin by neurons upon administration of nicotine has been reported by Hery et al., Arch. Int. Pharmacodyn. Ther., Vol. 296, pp. 91-97 (1977). Release of glutamate by neurons upon administration of nicotine has been reported by Toth et al., Neurochem Res., Vol. 17, pp. 265-271 (1992). Therefore, it would be desirable to provide a pharmaceutical composition containing an active ingredient having nicotinic pharmacology, which pharmaceutical composition is capable of illicting neurotransmitter release within a subject in order to prevent or treat a neurological disorder. In addition, nicotine reportedly potentiates the pharmacological behavior of certain pharmaceutical compositions used for the treatment of certain CNS disorders. See, Sanberg et al., Pharmacol. Biochem. and Behavior, Vol. 46, pp. 303-307 (1993); Harsing et al., J. Neurochem., Vol. 59, pp. 48-54 (1993) and Hughes, Proceedings from Intl. Symp. Nic., S40 (1994). Furthermore, various other beneficial pharmacological effects of nicotine have been proposed. See, Decina et al., Biol. Psychiatry, Vol. 28, pp. 502-508 (1990); Wagner et al., Pharmacopsychiatry, Vol. 21, pp. 301-303 (1988); Pomerleau et al., Addictive Behaviors, Vol. 9, p. 265 (1984); Onaivi et al., Life Sci., Vol. 54(3), pp. 193-202 (1994) and Hamon, Trends in Pharmacol. Res., Vol. 15, pp. 36-39.
It would be desirable to provide a useful method for the prevention and treatment of a CNS disorder by administering a nicotinic compound to a patient susceptible to or suffering from such a disorder. It would be highly beneficial to provide individuals suffering from certain CNS disorders with interruption of the symptoms of those diseases by the administration of a pharmaceutical composition which has nicotinic pharmacology and which has a beneficial effect upon the functioning of the CNS, but which does not provide any significant associated side effects (e.g., increased heart rate and blood pressure) attendant with interaction of that compound with cardiovascular sites. It would be highly desirable to provide a pharmaceutical composition incorporating a compound which interacts with nicotinic receptors which have the potential to affect the functioning of the CNS, but which does not significantly affect those receptors which have the potential to induce undesirable side effects (e.g., appreciable pressor cardiovascular effects and appreciable activity at skeletal muscle sites).
The present invention relates to aryl substituted aliphatic amine compounds, aryl substituted olefinic amine compounds and aryl substituted acetylenic amine compounds. A representative compound is (E)-N-methyl-5-(3-pyridinyl)-4-penten-2-amine.
The present invention relates to a method for providing prevention or treatment of a central nervous system (CNS) disorder. The method involves administering to a subject an effective amount of a compound of the present invention.
The present invention, in another aspect, relates to a pharmaceutical composition comprising an effective amount of a compound of the present invention. Such a pharmaceutical composition incorporates a compound which has the capability of interacting with relevant nicotinic receptor sites of a subject, and hence has the capability of acting as a therapeutic in the prevention or treatment of a CNS disorder.
The pharmaceutical compositions of the present invention are useful for the prevention and treatment of CNS disorders. The pharmaceutical compositions provide therapeutic benefit to individuals suffering from certain CNS disorders and exhibiting clinical manifestations of such disorders in that the compounds within those compositions have the potential to (i) exhibit nicotinic pharmacology and affect nicotinic receptors sites in the CNS (e.g., act as a pharmacological agonist to activate nicotinic receptors), and (ii) elicit neurotransmitter secretion, and hence prevent and suppress the symptoms associated with those diseases. In addition, the compounds are expected to have the potential to (i) increase the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects and (iii) not provide appreciable adverse side effects (e.g., significant increases in blood pressure and heart rate, and significant effects upon skeletal muscle). The pharmaceutical compositions of the present invention are believed to be safe and effective with regards to prevention and treatment of CNS disorders.
The present invention, in one aspect, relates to certain compounds having the formula: 
where X is nitrogen or carbon bonded to a substituent species characterized as having a sigma m value greater than 0, often greater than 0.1, generally greater than 0.2 and even greater than 0.3; less than 0 and generally less than xe2x88x920.1; or 0; as determined in accordance with Hansch et al., Chem. Rev., Vol. 91, pp. 165-195 (1991); n is an integer which is 1, 2, 3, 4, 5, 6 or 7, preferably is 1, 2 or 3, and most preferably is 2 or 3; Exe2x80x2 represents hydrogen or lower alkyl (e.g., straight chain or branched alkyl including C1-C5, such as methyl, ethyl or isopropyl) or halo substituted lower alkyl (e.g., straight chain or branched alkyl including C1-C5, such as trifluormethyl or trichloromethyl); Exe2x80x3 represents lower alkyl (e.g., straight chain or branched alkyl including C1-C5, such as methyl, ethyl or isopropyl) or halo substituted lower alkyl (e.g., straight chain or branched alkyl including C1-C5, such as trifluormethyl or trichloromethyl); Zxe2x80x2 and Zxe2x80x3 individually represent hydrogen or lower alkyl (e.g., straight chain or branched alkyl including C1-C5, such as methyl, ethyl or isopropyl), and preferably at least one of Zxe2x80x2 and Zxe2x80x3 is hydrogen, and most preferably Zxe2x80x2 is hydrogen and Zxe2x80x3 is methyl; alternatively Zxe2x80x2 is hydrogen and Zxe2x80x3 represents a ring structure, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, quinuclidinyl, pyridinyl, quinolinyl, pyrinidinyl, phenyl, alkyl or halo substituted phenyl, benzyl, or alkyl or halo substituted benzyl; alternatively Zxe2x80x2, Zxe2x80x3 and the associated nitrogen atom can form a ring structure, such as aziridinyl, azetidinyl, pyrollidinyl, piperidinyl, piperazinyl or morpholinyl; A, Axe2x80x2 and Axe2x80x3 individually represent hydrogen, alkyl (e.g., lower straight chain or branched alkyl, including C1-C7, but preferably methyl or ethyl) or halo (e.g., F, Cl, Br or I); the dashed line in the structure represents a Cxe2x80x94C single bond, a Cxe2x80x94C double bond or a Cxe2x80x94C triple bond; m is 0 or 1 when the dashed line is a Cxe2x80x94C single or Cxe2x80x94C double bond, and 0 when the dashed line is a Cxe2x80x94C triple bond; p is 0 or 1 when the dashed line is a Cxe2x80x94C single or Cxe2x80x94C double bond, and 0 when the dashed line is a Cxe2x80x94C triple bond; the wavy line in the structure represents a cis (Z) or trans (E) form of the compound when the dashed line is a Cxe2x80x94C double bond; and Xxe2x80x2 represents CH2 (m=0) or CHExe2x80x3 (m=1) when the dashed line is a Cxe2x80x94C single bond, CH or CExe2x80x3 when the dashed line is a Cxe2x80x94C double bond, and C when the dashed line is a Cxe2x80x94C triple bond. X includes N, Cxe2x80x94H, Cxe2x80x94F, Cxe2x80x94Cl, Cxe2x80x94Br, Cxe2x80x94I, Cxe2x80x94NRxe2x80x2Rxe2x80x3, Cxe2x80x94CF3, Cxe2x80x94OH, Cxe2x80x94CN, Cxe2x80x94C2Rxe2x80x2, Cxe2x80x94SH, Cxe2x80x94SCH3, Cxe2x80x94N3, Cxe2x80x94SO2CH3, Cxe2x80x94ORxe2x80x2, Cxe2x80x94SRxe2x80x2, Cxe2x80x94C(xe2x95x90O)N Rxe2x80x2Rxe2x80x3, Cxe2x80x94NRxe2x80x2C(xe2x95x90O)Rxe2x80x2, Cxe2x80x94(Cxe2x95x90O)Rxe2x80x2, Cxe2x80x94C(xe2x95x90O)ORxe2x80x2, xe2x80x94CCH2ORxe2x80x2, Cxe2x80x94OC(xe2x95x90O)Rxe2x80x2, COC(xe2x95x90O)NRxe2x80x2Rxe2x80x3 and Cxe2x80x94NRxe2x80x2C(xe2x95x90O)ORxe2x80x2 where Rxe2x80x2 and Rxe2x80x3 are individually hydrogen, lower alkyl (e.g., alkyl containing one to five carbon atoms, preferably methyl, ethyl or isopropyl), an aromatic group-containing species or a substituted aromatic group-containing species. When X represents a carbon atom bonded to a substituent species, that substitutent species often has a sigma m value which is between about xe2x88x920.3 and about 0.75, and frequently between about xe2x88x920.25 and about 0.6. In certain circumstances when X represents a carbon atom bonded to a substituent species, the dashed line is a Cxe2x80x94C double bond and the compound has the trans (E) form, the substituent species is characterized as having a sigma m value not equal to 0. Particularly when the dashed line is a Cxe2x80x94C double bond, the compound has the trans (E) form, A, Axe2x80x2, Axe2x80x3 and Zxe2x80x2 all are hydrogen, n is 2, and Zxe2x80x3 is hydrogen or methyl, the substituent species is characterized as having a sigma m value not equal to 0. Particularly when the dashed line is a Cxe2x80x94C double bond, the compound has the trans (E) form, A, Axe2x80x2, Axe2x80x3 and Zxe2x80x2 all are hydrogen, n is 2, and Zxe2x80x3 is hydrogen or methyl, at least one of Exe2x80x2 or Exe2x80x3 is lower alkyl or halo substituted lower alkyl. In addition, it is highly preferred that A is hydrogen, it is preferred that Axe2x80x2 is hydrogen, and normally Axe2x80x3 is hydrogen. Generally, both A and Axe2x80x2 are hydrogen; sometimes A and Axe2x80x2 are hydrogen, and Axe2x80x3 is methyl or ethyl; and often A, Axe2x80x2 and Axe2x80x3 are all hydrogen. Depending upon the identity and positioning of each individual Exe2x80x2 or Exe2x80x3, certain compounds can be optically active. Typically, the values of each of m and p, and the selection of Exe2x80x2, are such that up to about 4, and frequently up to 3, of the substituents designated as Exe2x80x2 and Exe2x80x3 are non-hydrogen substituents (i.e., substituents such as lower alkyl or halo-substituted lower alkyl).
Representative compounds are N-methyl-4-(3-pyridinyl)-2-methylbutan-1-amine, N-methyl-4-(3-pyridinyl)-3-methylbutan-1-amine, N-methyl-5-(3-pyridinyl)-pentan-1-amine, N-methyl-6-(3-pyridinyl)-hexan-3-amine, N-methyl-5-(3-pyridinyl)-2-methylpentan-2-amine, N-methyl-5-(3-pyridinyl)-3-methylpentan-2-amine, N-methyl-5-(3-pyridinyl)-pentan-2-amine, N-methyl-5-(3-pyridinyl)-1,1,1-trifluoropentan-2-amine, N-methyl-5-(3-pyridinyl)-4-methylpentan-1-amine, N-methyl-5-(3-pyridinyl)-4-methylpentan-2-amine, N-methyl-1-(3-pyridinyl)-octan-4-amine, N-methyl-1-(3-pyridinyl)-5-methylheptan-4-amine, N-methyl-6-(3-pyridinyl)-2,4-dimethylhexan-2-amine, N-methyl-6-(3-pyridinyl)-5-methylhexan-2-amine, N-methyl-6-(3-pyridinyl)-hexan-2-amine, N-methyl-6-(3-pyridinyl)-5-methylhexan-3-amine, 4-(3-pyridinyl)-2-methylbutan-1-amine, 4-(3-pyridinyl)-3-methylbutan-1-amine, 5-(3-pyridinyl)-pentan-1-amine, 6-(3-pyridinyl)-hexan-3-amine, 5-(3-pyridinyl)-2-methylpentan-2-amine, 5-(3-pyridinyl)-3-methylpentan-2-amine, 5-(3-pyridinyl)-pentan-2-amine, 5-(3-pyridinyl)-1,1,1-trifluoropentan-2-amine, 5-(3-pyridinyl)-4-methylpentan-1-amine, 5-(3-pyridinyl)-4-methylpentan-2-amine, 1-(3-pyridinyl)-octan-4-amine, 1-(3-pyridinyl)-3-methylheptan-5-amine, 6-(3-pyridinyl)-2,4-dimethylhexan-2-amine, 6-(3-pyridinyl)-5-methylhexan-2-amine, 6-(3-pyridinyl)-hexan-2-amine and 6-(3-pyridinyl)-5-methylhexan-3-amine.
Other representative compounds are N-methyl-5-(3-pyridinyl)-4-pentyn-2-amine, N-methyl-6-(3-pyridinyl)-5-hexyn-3-amine, N-methyl-1-(3-pyridinyl)-1-heptyn-4-amine, N-methyl-1-(3-pyridinyl)-1-octyn-4-amine, N-methyl-1-(3-pyridinyl)-1-nonyn-4-amine, N-methyl-5-(3-pyridinyl)-3-methyl-4-pentyn-2-amine, 5-(3-pyridinyl)-4-pentyn-2-amine, 6-(3-pyridinyl)-5-hexyn-3-amine, 1-(3-pyridinyl)-1-heptyn-4-amine, 1-(3-pyridinyl)-1-octyn-4-amine, 1-(3-pyridinyl)-1-nonyn-4-amine and 5-(3-pyridinyl)-3-methyl-4-pentyn-2-amine.
Of particular interest are compounds having the formula: 
where n, m, p, X, A, Axe2x80x2, Axe2x80x3, Exe2x80x2, Exe2x80x3, Zxe2x80x2 and Zxe2x80x3 are as defined hereinbefore, and those compounds can have the cis (Z) or trans (E) form. For such compounds of pariticular interest, X most preferably is nitrogen or carbon bonded to a substituent species characterized as having a sigma m value greater than 0, often greater than 0.1 generally greater than 0.2 and even greater than 0.3; less than 0 and generally less than xe2x88x920.1; or 0. One representative compound is (E)-N-methyl-4-[3-(5-ethoxypyridin)yl]-3)-buten-1-amine for which X is Cxe2x80x94OCH2CH3, n is 2, m is 0, p is 0, A, Axe2x80x2, Axe2x80x3 and Zxe2x80x2 each are hydrogen, all Exe2x80x2 are hydrogen and Zxe2x80x3 is methyl. Another representative compound is (E)-4-[3-(5-methoxypyridin)yl]-3-buten-1-amine for which X is Cxe2x80x94OCH3, n is 2, m is 0, p is 0, all Exe2x80x2 are hydrogen, and A, Axe2x80x2, Axe2x80x3, Zxe2x80x2 and Zxe2x80x3 each are hydrogen. Another representative compound is (E)-N-methyl-4-[3-(5-methoxypyridin)yl]-3-buten-1-amine for which X is Cxe2x80x94OCH3, n is 2, m is 0, p is 0, all Exe2x80x2 are hydrogen, and A, Axe2x80x2, Axe2x80x3, and Zxe2x80x2 are each hydrogen, and Zxe2x80x3 is methyl. Another representative compound is (E)-4-[3-(5-ethoxypyridin)yl]-3-buten-1-amine for which X is Cxe2x80x94OCH2CH3, n is 2, m is 0, p is 0, all Exe2x80x2 are hydrogen, and A, Axe2x80x2, Axe2x80x3, Zxe2x80x2 and Zxe2x80x3 each are hydrogen. Another representative compound is (E)-4-[3-(5-methoxy-6-methylpyridin)yl]-3-buten-1-amine for which X is Cxe2x80x94OCH3, n is 2, m is 0, p is 0, all Exe2x80x2 are hydrogen, Axe2x80x3 is methyl, and A, Axe2x80x2, Zxe2x80x2 and Zxe2x80x3 each are hydrogen. Another representative compound is (E)-N-methyl-4-[3-(5-methoxy-6-methylpyridin)yl]-3-buten-1-amine for which X is Cxe2x80x94OCH3, n is 2, m is 0, p is 0, all Exe2x80x2 are hydrogen, Axe2x80x3 and Zxe2x80x3 each are methyl, and A, Axe2x80x2 and Zxe2x80x2 each are hydrogen. Another representative compound is (E)-N-methyl-4-[3-(5-hydroxymethylpyridin)yl]-3-buten-1-amine for which X is xe2x80x94CCH2OH, n is 2, m is 0, p is 0, all Exe2x80x2 are hydrogen, Zxe2x80x2 is methyl and A, Axe2x80x2, Axe2x80x3 and Zxe2x80x3 each are hydrogen.
Other representative compounds are (E) and (Z)-N-methyl-4-(3-pyridinyl)-2-methyl-3-buten-1-amine, (E) and (Z)-N-methyl-4-(3-pyridinyl)-3-methyl-3-buten-1-amine, (E) and (Z)-N-methyl-6-(3-pyridinyl)-5-hexen-3-amine, (E) and (Z)-N-methyl-5-(3-pyridinyl)-2-methyl-4-penten-2-amine, (E) and (Z)-N-methyl-5-(3-pyridinyl)-3-methyl-4-penten-2-amine, (E) and (Z)-N-methyl-5-(3-pyridinyl)-4-penten-2-amine, (E) and (Z)-N-methyl-5-(3-pyridinyl)-1,1,1-trifluoro-4-penten-2-amine, (E) and (Z)-N-methyl-5-(3-pyridinyl)-4-methyl-4-penten-1-amine, (E) and (Z)-N-methyl-5-(3-pyridinyl)-4-methyl-4-penten-2-amine, (E) and (Z)-N-methyl-1-(3-pyridinyl)-1-octen-4-amine, (E) and (Z)-N-methyl-1-(3-pyridinyl)-5-methyl-1-hepten-4-amine, (E) and (Z)-N-methyl-6-(3-pyridinyl)-2,4-dimethyl-5-hexen-2-amine, (E) and (Z)-N-methyl-6-(3-pyridinyl)-5-methyl-5-hexen-2-amine, (E) and (Z)-N-methyl-6-(3-pyridinyl)-5-hexen-2-amine, (E) and (Z)-N-methyl-6-(3-pyridinyl)-5-methyl-5-hexen-3-amine, (E) and (Z)-4-(3-pyridinyl)-2-methyl-3-buten-1-amine, (E) and (Z)-4-(3-pyridinyl)-3-methyl-3-buten-1-amine, (E) and (Z)-6-(3-pyridinyl)-5-hexen-3-amine, (E) and (Z)-5-(3-pyridinyl)-2-methyl-4-penten-2-amine, (E) and (Z)-5-(3-pyridinyl)-3-methyl-4-penten-2-amine, (E) and (Z)-5-(3-pyridinyl)-4-penten-2-amine, (E) and (Z)-5-(3-pyridinyl)-1,1,1-trifluoro-4-penten-2-amine, (E) and (Z)-5-(3-pyridinyl)-4-methyl-4-penten-1-amine, (E) and (Z)-5-(3-pyridinyl)-4-methyl-4-penten-2-amine, (E) and (Z)-1-(3-pyridinyl)-1-octen-4-amine, (E) and (Z)-1-(3-pyridinyl)-3-methyl-5-hepten-1-amine, (E) and (Z)-6-(3-pyridinyl)-2,4-dimethyl-5-hexen-2-amine, (E) and (Z)-6-(3-pyridinyl)-5-methyl-5-hexen-2-amine, (E) and (Z)-6-(3-pyridinyl)-5-hexen-2-amine, and (E) and (Z)-6-(3-pyridinyl)-5-methyl-5-hexen-3-amine. For such representative compounds at least one of m or p are 1 and/or at least one of Exe2x80x2 is a non-hydrogen substituent.
The manner in which aryl substituted aliphatic amine compounds of the present invention are synthetically produced can vary. Preparation of various aryl substituted aliphatic amine compounds can be carried out using the types of techniques disclosed by Rondahl, Acta Pharm. Suec., Vol. 13, pp. 229-234 (1976). Certain metanicotine-type compounds that possess a saturated side chain rather than an olefinic side chain can be prepared by hydrogenation of the corresponding metanicotine-type compounds or the corresponding acetylenic precursors. For example, a dihydrometanicotine-type compound can be prepared by hydrogenation of an (E)-metanicotine-type compound using the types of procedures described by Kamimura et al., Agr. Biol. Chem., Vol. 27, No. 10, pp. 684-688 (1963).
The manner in which aryl substituted acetylenic amine compounds of the present invention are synthetically produced can vary. For example, an aryl substituted acetylenic amine compound, such as an N-methyl-4-(3-pyridinyl)-3-butyn-1-amine type compound, can be prepared using a series of synthetic steps: (i) conversion of 3-pyridinecarboxaldehyde to a 1,1-dihalo-2-(3-pyridinyl)-ethylene using a carbon tetrahalide and triphenylphosphine, (ii) side chain elaboration of this intermediate by reaction with butyl lithium and ethylene oxide, affording 4-(3-pyridinyl)-3-butyn-1-ol, (iii) conversion of this intermediate to its methanesulfonate ester, and (iv) mesylate displacement with methyl amine, affording an N-methyl-4-(3-pyridinyl)-3-butyn-1-amine type compound. Representative synthetic techniques for aryl substituted acetylenic compounds are set forth in U.S. patent application Ser. No. 08/364,979, filed Jan. 6, 1995, the disclosure of which is incorporated herein by reference. Representative alkylene oxides which can be employed include propylene oxide, 1,2-epoxybutane, 1,2-epoxypentane, 1,2-epoxyhexane, 1,2-epoxyheptane, (E)-2,3-epoxybutane and (Z)-2,3-epoxybutane. 5-Substituted-3-pyridinecarboxaldehydes, such as 5-ethoxy-3-pyridinecarboxaldehyde, also can be employed.
The manner in which aryl substituted olefinic amine compounds of the present invention are synthetically produced can vary. (E)-metanicotine-type compounds can be prepared using the techniques set forth by Lxc3x6ffler et al., Chem. Ber., Vol. 42, pp. 3431-3438 (1909) and Laforge, J.A.C.S., Vol. 50, p. 2477 (1928) from substituted nicotine-type compounds. Certain 6-substituted metanicotine-type compounds can be prepared from the corresponding 6-substituted nicotine-type compounds using the general methods of Acheson et al., J. Chem. Soc., Perkin Trans. 1, Vol. 2, pp. 579-585 (1980). The requisite precursors for such compounds, 6-substituted nicotine-type compounds, can be synthesized from 6-substituted nicotinic acid esters using the general methods disclosed by Rondahl, Acta Pharm. Suec., Vol. 14, pp 113-118 (1977). Preparation of certain 5-substituted metanicotine-type compounds can be accomplished from the corresponding 5-substituted nicotine-type compounds using the general method taught by Acheson et al., J. Chem. Soc., Perkin Trans. 1, Vol. 2, pp. 579-585 (1980). The 5-halo-substituted nicotine-type compounds (e.g., fluoro- and bromo-substituted nicotine-type compounds) and the 5-amino nicotine-type compounds can be prepared using the general procedures disclosed by Rondahl, Act. Pharm. Suec., Vol. 14, pp. 113-118 (1977). The 5-trifluoromethyl nicotine-type compounds can be prepared using the techniques and materials set forth in Ashimori et al., Chem. Pharm. Bull., Vol. 38(9), pp. 2446-2458 (1990) and Rondahl, Acta Pharm. Suec., Vol. 14, pp.113-118 (1977).
Furthermore, preparation of certain metanicotine-type compounds can be accomplished using a palladium catalyzed coupling reaction of an aromatic halide and a terminal olefin containing a protected amine substituent, removal of the protective group to obtain a primary amine, and optional alkylation to provide a secondary or tertiary amine. In particular, certain metanicotine-type compounds can be prepared by subjecting a 3-halo-substituted, 5-substituted pyridine compound or a 5-halo-substituted pyrimidine compound to a palladium catalyzed coupling reaction using an olefin possessing a protected amine functionality (e.g., such an olefin provided by the reaction of a phthalimide salt with 3-halo-1-propene, 4-halo-1-butene, 5-halo-1-pentene or 6-halo-1-hexene). See, Frank et al., J. Org. Chem., Vol. 43(15), pp. 2947-2949 (1978) and Malek et al., J. Org. Chem., Vol. 47, pp. 5395-5397 (1982). Alternatively, certain metanicotine-type compounds can be prepared by coupling an N-protected, modified amino acid residue, such as 4-(N-methyl-N-tert-butyloxycarbonyl)aminobutyric acid methyl ester, with an aryl lithium compound, as can be derived from a suitable aryl halide and butyl lithium. The resulting N-protected aryl ketone is then chemically reduced to the corresponding alcohol, converted to the alkyl halide, and subsequently dehydrohalogenated to introduce the olefin functionality. Removal of the N-protecting group then affords the desired metanicotine-type compound.
There are a number of different methods for providing (Z)-metanicotine-type compounds. In one method, (Z)-metanicotine-type compounds can be synthesized from nicotine-type compounds as a mixture of E and Z isomers; and the (Z)-metanicotine-type compounds can then be separated by chromatography using the types of techniques disclosed by Sprouse et al., Abstracts of Papers, p. 32, Coresta/TCRC Joint Conference (1972). In another method, metanicotine-type compounds can be prepared by the controlled hydrogenation of the corresponding acetylenic compound (e.g., an N-methyl-4-(3-pyridinyl)-3-butyn-1-amine type compound). For example, certain 5-substituted (Z)-metanicotine-type compounds and certain 6-substituted (Z)-metanicotine-type compounds can be prepared from 5-substituted-3-pyridinecarboxaldehydes and 6-substituted-3-pyridinecarboxaldehydes, respectively. Representative synthetic techniques for (Z)-metanicotine-type compounds are set forth in U.S. patent application Ser. No. 08/364,979.
There are yet other methods by which aryl substituted olefinic amine compounds of the present invention can be synthetically produced. An olefinic alcohol, such as 5-hexen-2-ol, is condensed with an aromatic halide, such as 3-bromopyridine or 3-iodopyridine. Typically, the types of procedures set forth in Frank et al., J. Org. Chem., Vol. 43, pp. 2947-2949 (1978) and Malek et al., J. Org. Chem., Vol. 47, pp. 5395-5397 (1982) involving a palladium-catalyzed coupling of an olefin and an aromatic halide are used. The olefinic alcohol optionally can be protected as a t-butyldimethylsilyl ether prior to the coupling. Desilylation then produces the olefinic alcohol. The alcohol condensation product then is converted to an amine using the type of procedures set forth in deCosta et al., J. Org. Chem., Vol. 35, pp. 4334-4343 (1992). Typically, the alcohol condensation product is converted to the aryl substituted olefinic amine by activation of the alcohol using methanesulfonyl chloride or p-toluenesulfonyl chloride, followed by mesylate or tosylate displacement using ammonia, or a primary or secondary amine. Thus, when the amine is ammonia, an aryl substituted olefinic primary amine compound is provided; when the amine is a primary amine such as methylamine or cyclobutylamine, an aryl substituted olefinic secondary amine compound is provided; and when the amine is a secondary amine such as dimethylamine or pyrrolidine, an aryl substituted olefinic tertiary amine compound is provided. Other representative olefinic alcohols include 4-penten-2-ol, 4-penten-1-ol, 5-hexen-3-ol, 3-methyl-3-buten-1-ol, 2-methyl-3-buten-1-ol, 2-methyl-4-penten-2-ol, 4-methyl-4-penten-1-ol, 4-methyl-4-penten-2-ol, 1-octen-4-ol, 5-methyl-1-hepten-4-ol, 4-methyl-5-hexen-2-ol, 5-methyl-5-hexen-2-ol, 5-hexen-2-ol and 5-methyl-5-hexen-3-ol. Trifluormethyl-substituted olefinic alcohols, such as 1,1,1-trifluoro-4-penten-2-ol, can be prepared from 1-ethoxy-2,2,2-trifluoro-ethanol and allyltrimethylsilane using the procedures of Kubota et al., Tetrahedron Letters, Vol. 33(10), pp. 1351-1354 (1992), or from trifluoroacetic acid ethyl ester and allyltributylstannane using the procedures of Ishihara et al., Tetrahedron Letters, Vol. 34(56), pp. 5777-5780 (1993). Certain olefinic alcohols are optically active, and can be used as enantiomeric mixtures or as pure enantiomers in order to provide the corresponding optically active forms of aryl substituted olefinic amine compounds. When an olefinic allylic alcohol, such as methallyl alcohol, is reacted with an aromatic halide, an aryl substituted olefinic aldehyde is produced; and the resulting aldehyde can be converted to an aryl substituted olefinic amine compound by reductive amination (e.g., by treatment using an alkyl amine and sodium cyanoborohydride). Preferred aromatic halides are 3-bromopyridine-type compounds and 3-iodopyridine-type compounds. Typically, substituent groups of such 3-halopyridine-type compounds are such that those groups can survive contact with those chemicals (e.g., tosylchloride and methylamine) and the reaction conditions experienced during the preparation of the aryl substituted olefinic amine compound. Alternatively, substituents such as xe2x80x94OH, xe2x80x94NH2 and xe2x80x94SH can be protected as corresponding acyl compounds, or substituents such as xe2x80x94NH2 can be protected as a phthalimide functionality.
The compounds of the present invention can be employed in a free base form or in a salt form (e.g., as pharmaceutically acceptable salts, such as chloride, perchlorate, ascorbate, sulfate, tartrate, fumarate, citrate, malate, lactate or aspartate salts). One method for providing the compound in salt form is set forth in of U.S. patent application Ser. No. 08/364,979. Another method for providing the compound in a fumaric salt form involves (i) dissolving one equivalent of the compound in ethanol, (ii) mixing the solution with two equivalents of fumaric acid, (iii) concentrating the resulting solution to dryness, (iv) dissolving the resulting solid in ethanol, and then (v) precipitating the monofumarate salt from the ethanol. Another method for providing the compound in a fumaric salt form involves (i) adding a solution of suitably pure compound dissolved in tetrahydrofuran to a refluxing solution of fumaric acid in a tetrahydrofuran/ethanol co-solvent mixture to form a precipitate, (ii) applying heat and additional ethanol to the the mixture to dissolve the precipitate, (iii) cooling the resulting solution, and seeding the solution if necessary, to cause precipitation of salt, and (iv) filtering and collecting the salt.
The present invention relates to a method for providing prevention of a CNS disorder to a subject susceptible to such a disorder, and for providing treatment to a subject suffering from a CNS disorder. In particular, the method comprises administering to a patient an amount of a compound effective for providing some degree of prevention of the progression of the CNS disorder (i.e., provide protective effects), amelioration of the symptoms of the CNS disorder, and amelioration of the reoccurrence of the CNS disorder. The method involves administering an effective amount of a compound selected from the general formulae which are set forth hereinbefore. The present invention relates to a pharmaceutical composition incorporating a compound selected from the general formulae which are set forth hereinbefore. Optically active compounds can be employed as racemic mixtures or as enantiomers. CNS disorders which can be treated in accordance with the present invention include presenile dementia (early onset Alzheimer""s disease), senile dementia (dementia of the Alzheimer""s type), Parkinsonism including Parkinson""s disease, Huntington""s chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette""s syndrome.
The pharmaceutical composition also can include various other components as additives or adjuncts. Exemplary pharmaceutically acceptable components or adjuncts which are employed in relevant circumstances include antioxidants, free radical scavenging agents, peptides, growth factors, antibiotics, bacteriostatic agents, immunosuppressives, buffering agents, anti-inflammatory agents, anti-pyretics, time release binders, anaesthetics, steroids and corticosteroids. Such components can provide additional therapeutic benefit, act to affect the therapeutic action of the pharmaceutical composition, or act towards preventing any potential side effects which may be posed as a result of administration of the pharmaceutical composition. In certain circumstances, a compound of the present invention can be employed as part of a pharmaceutical composition with other compounds intended to prevent or treat a particular CNS disorder.
The manner in which the compounds are administered can vary. The compounds can be administered by inhalation (e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Pat. No. 4,922,901 to Brooks et al.); topically (e.g., in lotion form); orally (e.g., in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within a solid carrier); intravenously (e.g., within a dextrose or saline solution); as an infusion or injection (e.g., as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids); or transdermally (e.g., using a transdermal patch). Although it is possible to administer the compounds in the form of a bulk active chemical, it is preferred to present each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration. Exemplary methods for administering such compounds will be apparent to the skilled artisan. For example, the compounds can be administered in the form of a tablet, a hard gelatin capsule or as a time release capsule. As another example, the compounds can be delivered transdermally using the types of patch technologies available from Ciba-Geigy Corporation and Alza Corporation. The administration of the pharmaceutical compositions of the present invention can be intermittent, or at a gradual, continuous, constant or controlled rate to a warm-blooded animal, such as a human being. In addition, the time of day and the number of times per day that the pharmaceutical formulation is administered can vary. Administration preferably is such that the active ingredients of the pharmaceutical formulation interact with receptor sites within the body of the subject that effect the functioning of the CNS.
The dose of the compound is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers. By xe2x80x9ceffective amountxe2x80x9d, xe2x80x9ctherapeutic amountxe2x80x9d or xe2x80x9ceffective dosexe2x80x9d is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder. Thus, an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject, and to elicit neuropharmacological effects (e.g., elicit neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder). Prevention of the disorder is manifested by delaying the onset of the symptoms of the disorder. Treatment of the disorder is manifested by a decrease in the symptoms associated with the disorder or an amelioration of the reoccurrence of the symptoms of the disorder.
The effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered. For human patients, the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1, often at least about 10, and frequently at least about 25 mg/24 hr./patient. For human patients, the effective dose of typical compounds requires administering the compound which generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 mg/24 hr./patient. In addition, administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 ng/ml, and frequently does not exceed 100 ng/ml.
The compounds useful according to the method of the present invention have the ability to pass across the blood-brain barrier of the patient. As such, such compounds have the ability to enter the central nervous system of the patient. The log P values of typical compounds useful in carrying out the present invention generally are greater than 0, often are greater than about 0.5, and frequently are greater than about 1. The log P values of such typical compounds generally are less than about 3.0, and generally are less than about 2.5. Log P values provide a measure of the ability of a compound to pass across a diffusion barrier, such as a biological membrane. See, Hansch, et al., J. Med. Chem., Vol. 11, p. 1 (1968).
The compounds useful according to the method of the present invention have the ability to bind to, and cause activation of, nicotinic cholinergic receptors of the brain of the patient. As such, such compounds have the ability to express nicotinic pharmacology, and in particular, to act as nicotinic agonists. The receptor binding constants of typical compounds useful in carrying out the present invention generally exceed about 1 nM, and often exceed about 5 nM. The receptor binding constants of such typical compounds generally are less than about 10 uM, often are less than about 1 uM, and frequently are less than about 100 nM. Receptor binding constants provide a measure of the ability of the compound to bind to half of the relevant receptor sites of certain brain cells of the patient. See, Cheng, et al., Biochem. Pharmacol., Vol. 22, pp. 3099-3108 (1973).
The compounds useful according to the method of the present invention have the ability to demonstrate a nicotinic function by effectively eliciting ion flux through, and neurotransmitter secretion from, nerve ending preparations (i.e., thalamic or striatal synaptosomes). As such, such compounds have the ability to cause relevant neurons to become activated, and to release or secrete acetylcholine, dopamine, and other neurotransmitters. Generally, typical compounds useful in carrying out the present invention effectively provide for relevant receptor activation in amounts of at least about 30 percent, often at least about 50 percent, and frequently at least about 75 percent, of that maximally provided by (S)-(xe2x88x92)-nicotine. Generally, typical compounds useful in carrying out the present invention are more potent than (S)-(xe2x88x92)-nicotine in eliciting relevant receptor activation. Generally, typical compounds useful in carrying out the present invention effectively provide for the secretion of dopamine in amounts of at least about 50 percent, often at least about 75 percent, and frequently at least about 100 percent, of that maximally provided by (S)-(xe2x88x92)-nicotine. Certain compounds of the present invention can provide secretion of dopamine in an amount which can exceed that maximally provided by (S)-(xe2x88x92)-nicotine. Generally, typical compounds useful in carrying out the present invention are less potent than (S)-(xe2x88x92)-nicotine in eliciting neurotransmitter secretion, such as dopamine secretion.
The compounds of the present invention, when employed in effective amounts in accordance with the method of the present invention, lack the ability to elicit activation of nicotinic receptors of human muscle to any significant degree. In that regard, the compounds of the present invention demonstrate poor ability to cause isotopic rubidium ion flux through nicotinic receptors in cell preparations derived from muscle preparations. Thus, such compounds exhibit receptor activation constants or EC50 values (i.e., which provide a measure of the concentration of compound needed to activate half of the relevant receptor sites of the skeletal muscle of a patient) which are extremely high (i.e., greater than about 1 mM). Generally, typical compounds useful in carrying the present invention activate isotopic rubidium ion flux by less than 5 percent of that maximally provided by (S)-(xe2x88x92)-nicotine.
The compounds of the present invention, when employed in effective amounts in accordance with the method of the present invention, are selective to certain relevant nicotinic receptors, but do not cause significant activation of receptors associated with undesirable side effects. By this is meant that a particular dose of compound resulting in prevention and/or treatment of a CNS disorder, is essentially ineffective in eliciting activation of certain ganglionic-type nicotinic receptors. This selectivity of the compounds of the present invention against those receptors responsible for cardiovascular side effects is demonstrated by a lack of the ability of those compounds to activate nicotinic function of adrenal chromaffin tissue. As such, such compounds have poor ability to cause isotopic rubidium ion flux through nicotinic receptors in cell preparations derived from the adrenal gland. Generally, typical compounds useful in carrying the present invention activate isotopic rubidium ion flux by less than 10 percent, often by less than 5 percent, of that maximally provided by S(xe2x88x92) nicotine.
Compounds of the present invention, when employed in effective amounts in accordance with the method of the present invention, are effective towards providing some degree of prevention of the progression of CNS disorders, amelioration of the symptoms of CNS disorders, and amelioration to some degree of the reoccurrence of CNS disorders. However, such effective amounts of those compounds are not sufficient to elicit any appreciable side effects, as is demonstrated by decreased effects on preparations believed to reflect effects on the cardiovascular system, or effects to skeletal muscle. As such, administration of compounds of the present invention provides a therapeutic window in which treatment of certain CNS disorders is provided, and side effects are avoided. That is, an effective dose of a compound of the present invention is sufficient to provide the desired effects upon the CNS, but is insufficient (i.e., is not at a high enough level) to provide undesirable side effects. Preferably, effective administration of a compound of the present invention resulting in treatment of CNS disorders occurs upon administration of less than ⅕, and often less than {fraction (1/10)}, that amount sufficient to cause any side effects to a significant degree.
The following example is provided in order to further illustrate various embodiments of the invention but should not be construed as limiting the scope thereof. Unless otherwise noted, all parts and percentages are by weight.